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Fibrocytes in the Tumor Microenvironment

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Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1224))

Abstract

Tumors have long been compared to chronic wounds that do not heal, since they share many of the same molecular and cellular processes. In normal wounds, healing processes lead to restoration of cellular architecture, while in malignant tumors, these healing processes become dysregulated and contribute to growth and invasion of neoplastic cells into the surrounding tissues. Fibrocytes are fibroblast-like cells that differentiate from bone marrow-derived CD14+ circulating monocytes and aid wound healing. Although most monocytes will differentiate into macrophages after extravasating into a tissue, signals present in a wound environment can cause some monocytes to differentiate into fibrocytes. The fibrocytes secrete matrix proteins and inflammatory cytokines, activate local fibroblasts to proliferate and increase extracellular matrix production, and promote angiogenesis, and because fibrocytes are contractile, they also help wound contraction. There is now emerging evidence that fibrocytes are present in the tumor microenvironment, attracted by the chronic tissue damage and cytokines from both cancer cells and other immune cells. Fibrocytes may aid in the survival and spread of neoplastic cells, so these wound-healing cells may be a promising target for anticancer research in future studies.

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References

  1. Flier JS, Underhill LH, Dvorak HF (1986) Tumors: wounds that do not heal. N Engl J Med 315(26):1650–1659. https://doi.org/10.1056/NEJM198612253152606

    Article  Google Scholar 

  2. Paget J (1871) Lectures on surgical pathology. Lindsay and Blakiston, Philadelphia

    Google Scholar 

  3. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1(1):71

    Article  CAS  Google Scholar 

  4. Chesney J, Metz C, Stavitsky AB, Bacher M, Bucala R (1998) Regulated production of Type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 160(1):419–425

    CAS  PubMed  Google Scholar 

  5. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166(12):7556–7562

    Article  CAS  Google Scholar 

  6. Hartlapp I, Abe R, Saeed RW et al (2001) Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. FASEB J 15(12):2215–2224. https://doi.org/10.1096/fj.01-0049com

    Article  CAS  PubMed  Google Scholar 

  7. Pilling D, Fan T, Huang D, Kaul B, Gomer RH (2009) Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One 4(10):e7475. https://doi.org/10.1371/journal.pone.0007475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171(1):380

    Article  CAS  Google Scholar 

  9. Chesney J, Bacher M, Bender A, Bucala R (1997) The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci U S A 94(12):6307–6312

    Article  CAS  Google Scholar 

  10. Iqbal SA, Sidgwick GP, Bayat A (2012) Identification of fibrocytes from mesenchymal stem cells in keloid tissue: a potential source of abnormal fibroblasts in keloid scarring. Arch Dermatol Res 304(8):665–671. https://doi.org/10.1007/s00403-012-1225-5

    Article  CAS  PubMed  Google Scholar 

  11. Yang L, Scott PG, Dodd C et al (2005) Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen 13(4):398–404. https://doi.org/10.1111/j.1067-1927.2005.130407.x

    Article  PubMed  Google Scholar 

  12. Mehrad B, Burdick MD, Zisman DA, Keane MP, Belperio JA, Strieter RM (2007) Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 353(1):104–108. https://doi.org/10.1016/j.bbrc.2006.11.149

    Article  CAS  PubMed  Google Scholar 

  13. Verstovsek S, Manshouri T, Pilling D et al (2016) Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. J Exp Med 213(9):1723–1740. https://doi.org/10.1084/jem.20160283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Galligan CL, Fish EN (2012) Circulating fibrocytes contribute to the pathogenesis of collagen antibody-induced arthritis. Arthritis Rheum 64(11):3583–3593. https://doi.org/10.1002/art.34589

    Article  CAS  PubMed  Google Scholar 

  15. Douglas RS, Afifiyan NF, Hwang CJ et al (2010) Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 95(1):430–438. https://doi.org/10.1210/jc.2009-1614

    Article  CAS  PubMed  Google Scholar 

  16. Kirchmann TTT, Prieto VG, Smoller BR (1994) CD34 staining pattern distinguishes basal cell carcinoma from trichoepithelioma. Arch Dermatol 130(5):589–592. https://doi.org/10.1001/archderm.1994.01690050057008

    Article  CAS  PubMed  Google Scholar 

  17. Chauhan H, Abraham A, Phillips JRA, Pringle JH, Walker RA, Jones JL (2003) There is more than one kind of myofibroblast: analysis of CD34 expression in benign, in situ, and invasive breast lesions. J Clin Pathol 56(4):271–276. https://doi.org/10.1136/jcp.56.4.271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Suster S, Fisher C (1997) Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors. Am J Surg Pathol 21(2):195

    Article  CAS  Google Scholar 

  19. Barth PJ, Ebrahimsade S, Hellinger A, Moll R, Ramaswamy A (2002) CD34+ fibrocytes in neoplastic and inflammatory pancreatic lesions. Virchows Arch 440(2):128–133. https://doi.org/10.1007/s00428-001-0551-3

    Article  CAS  PubMed  Google Scholar 

  20. Barth PJ, Ebrahimsade S, Ramaswamy A, Moll R (2002) CD34+ fibrocytes in invasive ductal carcinoma, ductal carcinoma in situ, and benign breast lesions. Virchows Arch 440(3):298–303. https://doi.org/10.1007/s004280100530

    Article  CAS  PubMed  Google Scholar 

  21. Barth P, Ramaswamy A, Moll R (2002) CD34 + fibrocytes in normal cervical stroma, cervical intraepithelial neoplasia III, and invasive squamous cell carcinoma of the cervix uteri. Virchows Arch 441(6):564–568. https://doi.org/10.1007/s00428-002-0713-y

    Article  PubMed  Google Scholar 

  22. Barth PJ, Schenck zu Schweinsberg T, Ramaswamy A, Moll R (2004) CD34+ fibrocytes, α-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx. Virchows Arch 444(3):231–234. https://doi.org/10.1007/s00428-003-0965-1

    Article  CAS  PubMed  Google Scholar 

  23. Nimphius W, Moll R, Olbert P, Ramaswamy A, Barth PJ (2007) CD34+ fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder. Virchows Arch 450(2):179–185. https://doi.org/10.1007/s00428-006-0347-6

    Article  CAS  PubMed  Google Scholar 

  24. Catteau X, Simon P, Vanhaeverbeek M, Noël J-C (2013) Variable stromal periductular expression of CD34 and smooth muscle actin (SMA) in intraductal carcinoma of the breast. PLoS One 8(3):e57773. https://doi.org/10.1371/journal.pone.0057773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ebrahimsade S, Westhoff CC, Barth PJ (2007) CD34+ fibrocytes are preserved in most invasive lobular carcinomas of the breast. Pathol Res Pract 203(9):695–698. https://doi.org/10.1016/j.prp.2007.05.009

    Article  PubMed  Google Scholar 

  26. Ramaswamy A, Moll R, Barth PJ (2003) CD34+ fibrocytes in tubular carcinomas and radial scars of the breast. Virchows Arch Int J Pathol 443(4):536–540. https://doi.org/10.1007/s00428-003-0855-6

    Article  Google Scholar 

  27. Chu GC, Kimmelman AC, Hezel AF, DePinho RA (2007) Stromal biology of pancreatic cancer. J Cell Biochem 101(4):887–907. https://doi.org/10.1002/jcb.21209

    Article  CAS  PubMed  Google Scholar 

  28. Fujisawa T, Joshi B, Nakajima A, Puri RK (2009) A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis. Cancer Res 69(22):8678–8685. https://doi.org/10.1158/0008-5472.CAN-09-2100

    Article  CAS  PubMed  Google Scholar 

  29. Barderas R, Bartolomé RA, Fernandez-Aceñero MJ, Torres S, Casal JI (2012) High expression of IL-13 receptor α2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis. Cancer Res 72(11):2780–2790. https://doi.org/10.1158/0008-5472.CAN-11-4090

    Article  CAS  PubMed  Google Scholar 

  30. Fujisawa T, Joshi BH, Puri RK (2012) IL-13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer. Int J Cancer 131(2):344–356. https://doi.org/10.1002/ijc.26366

    Article  CAS  PubMed  Google Scholar 

  31. Todaro M, Lombardo Y, Francipane MG et al (2008) Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ 15(4):762–772. https://doi.org/10.1038/sj.cdd.4402305

    Article  CAS  PubMed  Google Scholar 

  32. Prokopchuk O, Liu Y, Henne-Bruns D, Kornmann M (2005) Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions. Br J Cancer 92(5):921. https://doi.org/10.1038/sj.bjc.6602416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Joshi BH, Leland P, Lababidi S, Varrichio F, Puri RK (2014) Interleukin-4 receptor alpha overexpression in human bladder cancer correlates with the pathological grade and stage of the disease. Cancer Med 3(6):1615–1628. https://doi.org/10.1002/cam4.330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D (2008) Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 83(6):1323–1333. https://doi.org/10.1189/jlb.1107782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vong S, Kalluri R (2011) The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis. Genes Cancer 2(12):1139–1145. https://doi.org/10.1177/1947601911423940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mahadevan D, Von Hoff DD (2007) Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther 6(4):1186

    Article  CAS  Google Scholar 

  37. Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R (2004) Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 36(4):598–606

    Article  CAS  Google Scholar 

  38. Sawai H, Okada Y, Funahashi H et al (2008) Basement membrane proteins play an important role in the invasive processes of human pancreatic cancer cells. J Surg Res 144(1):117–123. https://doi.org/10.1016/j.jss.2007.03.023

    Article  CAS  PubMed  Google Scholar 

  39. Shintani Y, Hollingsworth MA, Wheelock MJ, Johnson KR (2006) Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH2-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res 66(24):11745

    Article  CAS  Google Scholar 

  40. Koenig A, Mueller C, Hasel C, Adler G, Menke A (2006) Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res 66(9):4662

    Article  CAS  Google Scholar 

  41. Mollenhauer J, Roether I, Kern HF (1987) Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas 2(1):14

    Article  CAS  Google Scholar 

  42. Vaquero EC, Edderkaoui M, Nam KJ, Gukovsky I, Pandol SJ, Gukovskaya AS (2003) Extracellular matrix proteins protect pancreatic cancer cells from death via mitochondrial and nonmitochondrial pathways. Gastroenterology 125(4):1188–1202

    Article  CAS  Google Scholar 

  43. Edderkaoui M, Hong P, Vaquero EC et al (2005) Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase. Am J Physiol Gastrointest Liver Physiol 289(6):G1137

    Article  CAS  Google Scholar 

  44. Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S (2004) Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 28(1):38

    Article  CAS  Google Scholar 

  45. Armstrong T, Packham G, Murphy LB et al (2004) Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res 10(21):7427

    Article  CAS  Google Scholar 

  46. Terai S, Fushida S, Tsukada T et al (2015) Bone marrow derived “fibrocytes” contribute to tumor proliferation and fibrosis in gastric cancer. Gastric Cancer 18(2):306–313. https://doi.org/10.1007/s10120-014-0380-0

    Article  CAS  Google Scholar 

  47. Mitsuhashi A, Goto H, Saijo A et al (2015) Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab. Nat Commun 6:8792. https://doi.org/10.1038/ncomms9792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 133(3421):571–573. https://doi.org/10.1016/S0140-6736(00)49915-0

    Article  Google Scholar 

  49. van Deventer HW, Wu QP, Bergstralh DT et al (2008) C-C chemokine receptor 5 on pulmonary fibrocytes facilitates migration and promotes metastasis via matrix metalloproteinase 9. Am J Pathol 173(1):253–264. https://doi.org/10.2353/ajpath.2008.070732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van Deventer HW, Palmieri DA, Wu QP, McCook EC, Serody JS (2013) Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C+ monocytes via CCL2. J Immunol 190(9):4861–4867. https://doi.org/10.4049/jimmunol.1202857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hirai H, Fujishita T, Kurimoto K et al (2014) CCR1-mediated accumulation of myeloid cells in the liver microenvironment promoting mouse colon cancer metastasis. Clin Exp Metastasis 31(8):977–989. https://doi.org/10.1007/s10585-014-9684-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shi Y, Ou L, Han S et al (2014) Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes. Oncogene 3:e129. https://doi.org/10.1038/oncsis.2014.44

    Article  CAS  Google Scholar 

  53. Zhang H, Maric I, DiPrima MJ et al (2013) Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122(7):1105–1113. https://doi.org/10.1182/blood-2012-08-449413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Darrell Pilling for helpful comments on the manuscript. This work was supported by NIH HL132919.

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Authors and Affiliations

  1. Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA

    David Roife

  2. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    David Roife & Jason B. Fleming

  3. Department of Biology/ILSB, Texas A&M University, College Station, TX, USA

    Richard H. Gomer

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  1. David Roife
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  2. Jason B. Fleming
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Correspondence to Richard H. Gomer .

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Editors and Affiliations

  1. Columbia University Medical Center, Department of Radiology, New York, NY, USA, Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

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Roife, D., Fleming, J.B., Gomer, R.H. (2020). Fibrocytes in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1224. Springer, Cham. https://doi.org/10.1007/978-3-030-35723-8_6

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